The present application is the national stage under 35 U.S.C. 371 of international application PCT/IL99/00436, filed Aug. 11, 1999 which designated the United States, which international application was published under PCT Article 21 (2) in English.
The present invention relates to a new process for the preparation of acetylcholinesterase inhibitors (anti-AchE) such as Donepezil, to some novel intermediates used in this process and to their preparation.
Dementia is a chronic progressive organic mental disorder in which there is disturbance of multiple higher cortical functions including memory, thinking, orientation, comprehension, calculation, learning capacity, language and judgement. Alzheimer""s Disease is the commonest cause of dementia and is characterized by degeneration of specific nerve cells, presence of neurotic plaques, and neurofibrillary tangles. Definitive diagnosis of Alzheimer""s Disease requires demonstration of these characteristic pathological features in brain tissue, although in the vast majority of cases diagnosis is made on clinical grounds alone, where it is more correctly called Senile Dementia of the Alzheimer Type (SDAT).
Various attempts have been made to treat the senile dementia with a drug. It was found that compounds of formula [X] (Scheme 1) possess a high acetylcholinesterase inhibitory activity (Sugimoto, H., et al., J. Med. Chem., v. 38, 481 (1995). One of the most potent acetylcholinesterase inhibitors (anti-AChE) of this class is Donepezil (E2020) [VII]. 
Donepezil is a new drug treatment for use in mild to moderate dementia due to SDAT. Donepezil acts by inhibiting acetylcholine esterase, the enzyme responsible for metabolising acetylcholine, thereby enhancing neurotransmitter levels.
The general synthetic route to compounds [X] comprises the condensation of cyclic aromatic ketones [XI] with 1-substituted-4-(xcfx89-formylalkyl)piperidines [XII] followed by reduction of the obtained compounds [XIII] (Scheme 1) (Sugimoto, H., et al., J. Med. Chem., v. 38, 481 (1995); Eisai Co., U.S. Pat. No. 5,100,901). 
The present invention relates to a process for preparing a compound of formula [I] or a salt thereof: 
wherein:
R1 is N-acyl-4-piperidyl; N-alkoxycarbonyl-4-piperidyl; 4-piperidyl; N-alkyl-4-piperidyl; N-benzyl-4-piperidyl; N-(xcfx89-aralkyl)-4-piperidyl; 4-pyridyl;
R4, R5, R6 and R7 are identical or different and each represents hydrogen, straight-chain or branched alkyl, aryl, hydroxy, alkoxy, aryloxy, benzyloxy, acyloxy, alkylthio, arylthio, benzylthio, acylamino, phthalimido or halogen;
n is 1, 2 or 3;
m is 1, 2, 3, 4 or 5;
which process comprises cyclisation of a compound of formula [II] or salts thereof 
wherein
R1, R4, R5, R6 and R7, m and n are as defined above;
R2 is selected from a derivatised or non-derivatised carboxyl, cyano, N-substituted aminocarbonyl groups or hydrogen;
R3 is selected from a derivatised or non-derivatised carboxyl, cyano or N-substituted aminocarbonyl groups, optionally in the presence of acids and/or solvents.
According to the present invention, enantiomerically enriched compounds of formula [I] or salts thereof are prepared by cyclisation of optically pure compounds of formula [II], wherein R2 and R3 are different.
The present invention also relates to new compounds of formula [II]: 
wherein
R1, R2, R3, R4, R5, R6 and R7, m and n are as defined above, including salts thereof and the optically active enantiomers thereof, with the proviso that when R1 is 4-pyridyl, and n=m=1, then at least one of R4, R5, R6 and R7 does not represent hydrogen or lower alkyl.
The present invention further relates to a process for preparing a compound [II] by the hydrogenation of a compound of formula [VIII] or [IX] or mixtures thereof 
wherein
R1, R3, R4, R5, R6, R7, n and m are as defined above.
Alternatively, a compound of the formula [II] can be prepared by reaction of a compound of formula [V]
with a compound of the formula [VI]
in the presence of a strong base,
wherein in all the above formulae, R1, R2, R3, R4, R5, R6, R7, X, m and n are as defined above.
Alternatively, a compound of the formula [II] can be prepared by reacting of compound of formula [III]
wherein
X is a facile leaving group,
with a compound of the formula [IV]
in the presence of a strong base as it was shown in one example by Miyoshi, Hideto et. al. (J. Biol. Chem., (1998), 273 (28).
The compounds of formula [I] and formula [II] can be prepared as described in the following reaction schemes and discussion. Unless otherwise indicated, the meanings R1, R2, R3, R4, R5, R6, R7, X, n and m in compounds of the formulae [I], [Ia], [II], [IIa], [III], [IIIa], [IV], [IVa], [V], [V], [VI], [VII], [IX], [XX], [XX], [VIIa], [IXa], [XVIIIa], [XIXa] which are shown or mentioned in the reaction schemes and discussion tat follow, are as defined above.
Scheme 2 below refers to a process for the preparation of a compound of formula [I] or salts thereof by cyclisation of a compound of formula [II] or salts thereof: 
When the above process is carried out with an optically pure compound of formula [II], (R2 and R3 are different), the obtained product is an enantiomically enriched compound of formula [I] or salts thereof.
According to the present invention ester, amido, cyano or ether protecting groups can be hydrolyzed under the conditions of the cyclisation reaction either in the starting compound [II] or in the desired compound [I].
Preferably, the cyclisation is carried out with a previously hydrolysed compound [II], wherein R2 is hydrogen or a carboxyl group and to R3 is a carboxyl group. Compound [II] wherein R2 and R3 are carboxyl groups, are decarboxylated in the course of the intramolecular acylatin.
More preferably, said cyclisation of compound [II] (R2=H, R3=COOH) is carried out under Friedel-Crafts reaction conditions, optionally with previous derivatisation of the R3 carboxylic group to a halocarbonyl group.
Preferably, the cyclisation of the present invention is carried out in the presence of protic acids or Lewis acids or a mixture thereof. Examples of such acids are trifluoromethanesulfonic acid, methanesulfonic acid, polyphosphoric acid, fluoro- or chlorosulfonic acid, sulfuric acid, hydrogen fluoride, hydrogen chloride, zinc chloride, zinc bromide, aluminium chloride, aluminium bromide, titanium chloride, boron fluoride, phosphorus pentoxide, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, thyonyl chloride and sulfuryl chloride.
The cyclisaton of the present invention can be carried out in the presence of a solvent. Preferably, the solvent is selected from dichloromethane, chloroform, dichloroethane, tetrachloroethane, chlorobenzene, dichlorobenzene, nitromethane, nitroethane, nitrobenzene, ether or mixtures thereof.
Pharmaceutically important compounds of formula [Ia] are obtained according to Scheme 3: 
Acids of formula [XV] or [XVI], which are obtained by hydrolysis of the corresponding esters [XIV] and [XVII], undergo cyclisation to yield Donepezil [VII] in high yield and purity (Scheme 4). 
According to another aspect, the present invention relates to new compounds of formula [II] including the optically active enantiomers thereof (R2xe2x89xa0R3) which are used in the cyclisation shown in Scheme 2 above.
Schemes 5 and 6 below refer to processes for preparation of the new compounds of formula [II]. 
Referring to Scheme 5 and 6, the compounds of formulae [III], [IV], [V], [VI], [XVIII], [XIX], [XX], [XXI] can be prepared by methods well known to those of ordinary skill in the art.
In the above formulae (Scheme 5), X represents a facile leaving group and may be a sulfonate group or a halogen. Preferably, X is selected from chlorine and bromine.
The reactions according to Scheme 5 are usually carried out in the presence of a strong base, as for example metal alkoxides, metal amides, metal hydrides or mixtures thereof. Most preferably, the strong base is selected from sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydride, sodium tert-pentoxide, sodium bis(trimethylsilyl)amide, lithium diisopropylamide or mixtures thereof.
The coupling reaction according to Scheme 6 is usually carried out in the presence of a base. Preferably, the base is selected from metal carbonate, metal alkoxides, metal amides or metal hydrides. More preferably, the base is selected from potassium carbonate, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydride, lithium diisopropylamide or mixture thereof.
The products of the coupling reaction shown in Scheme 6, i.e compounds [VIII] and [IX] can undergo isomerisation under the reaction conditions to give either an isomeric mixture or the thermodynamically more stable isomer.
The above process can be carried out either without a solvent or in the presence of an organic solvent or water. The organic solvent is preferably selected from tetrahydrofuran (THF), 1,2-dimethoxyethane, dichloromethane, benzene, toluene, N,N-dimethylformamide (DMF), N,N-dimethylacetamide, 1-methyl-2-pyrrolidinone, dimethylsulphoxide (DMSO), methanol, ethanol, isopropanol, tert-butyl alcohol or mixtures thereof.
The compounds [VIII] and [IIX] in Scheme 6 can be reduced by catalytic hydrogenation. Transition metals can be used as catalysts in said catalytic hydrogenation. Preferably, Pd, Pt, Rh, Ru or Ni are used. During this process some of the R1 groups are reduced (e.g. 4-pyridylxe2x80x94to 4-piperidyl. In such a case it is preferred to protect the nitrogen of the piperidyl group).
A compound of formula [IIa] (Scheme 3) may be prepared from the compounds [IIIa] and [IVa], as shown in the following Schemes 7 and 8. 
Compounds [XIV] and [XVII] which can be used in the synthesis of Donepezil (Scheme 4) may be prepared according to either Scheme 9 or Scheme 10. 
Enantiomerically enriched compounds of formula [I] are obtained from optically pure compounds [II] (Scheme 2), which in turn, are obtained from a racemic mixture of [II] (wherein R2xe2x89xa0R3) by either of the following reactions:
Diastereomeric crystallisation with optically pure acids, followed by several recrystallisations and recovery of the desired product;
Diastereomeric crystallisation with optically pure amines (if R2 or R3=COOH) followed by a number of recrystallisations and recovery of the desired product;
Resolution on an optically active sorbent;
Enzymatic resolution.
Furthermore, in order to increase the yield of the optically pure product [II], the undesired enantiomer may be racemised and reused.